Synthetic absorbable polyesters are well known in the art. The terms absorbable, bioabsorbable, bioresorbable, resorbable, biodegradable are used herein interchangeably. The open and patent literature particularly describe polymers and copolymers made from glycolide, L(−)-lactide, D(+)-lactide, meso-lactide, epsilon-caprolactone, p-dioxanone, and trimethylene carbonate.
A very important aspect of any absorbable medical device is the length of time that its mechanical properties are retained in vivo. For example, in some surgical applications it is important for the device to retain strength for a considerable length of time in order to allow the body the time necessary to heal while performing its desired function. Such slow healing situations include, for example, diabetic patients or bodily areas having poor or diminished blood supply. Absorbable long term sutures are known and have been made from conventional polymers, primarily from lactide. Examples include a braided suture made from a high-lactide, lactide/glycolide copolymer. Those skilled in the art will appreciate that monofilament and multifilament absorbable sutures exist in the art and that short term and long term absorbable sutures also exist in the art. Long term functioning may be described as retaining a certain amount of mechanical integrity in vivo beyond 10 to 12 weeks post-implantation.
Medical devices in the form of polymeric foams or films are known in the art. What does not presently exist is an absorbable polymer that can be made into a foam that is soft enough to exhibit mechanical elasticity to provide both spring-back when compressed and superior handling characteristics to the surgeon, yet maintain its mechanical properties post-implantation to function effectively long term while fully absorbing. There then remains the problem of providing such a polymer that can meet these needs. There is also a need for an absorbable surgical foam made from such a polymer. Absorbable foams generally come in two basic forms, open cell structures and closed cell structures. Open cell foams are particularly advantageous for tissue engineering applications requiring cell ingrowth. Buttress designs of various sorts have been described for use with mechanical surgical staplers, but an implantable absorbable foam buttress has yet to be provided that meets long term needs.
Foam formation from polymeric materials has been described by various researchers over the years. For instance, foams have been made by melt processes such as extrusion with blowing agents and utilizing supercritical carbon dioxide.
For example, the use of supercritical carbon dioxide in making foams is disclosed in “Formation and size distribution of pores in poly(ε-caprolactone) foams prepared by pressure quenching using supercritical CO2”, Karimi, et. al, J. of Supercritical Fluids 61 (2012) 175-190. The use of supercritical carbon dioxide in making foams is also disclosed in “Supercritical Carbon Dioxide: Putting the Fizz into Biomaterials”, Barry, et. al, Phil. Trans. R. Soc. A 2006 364, 249-261.
Lyophilization is well known in the art and has been used to prepare foams from synthetic absorbable materials. This process is not without difficulties, however. The polymer to be lyophilized must be soluble in the selected solvent, and there are only a limited number of solvents that are suitable for the lyophilization process. The freezing point of a successful solvent needs to be above that of a reasonable shelf and condenser temperature (˜−70° C.), and low enough to conveniently dissolve the resin to be lyophilized. Moreover, the vapor pressure at low temperature needs to be high enough so that the solvent can be sublimated from the frozen state at a reasonable enough rate. Typical solvents conventionally used in lyophilization processes include water, 1,4-dioxane, DMSO, DMF, and certain alcohols. Most absorbable polyesters are hydrophobic in nature while the solvents suitable for lyophilization tend to be polar in nature; this creates solubility issues as it is the rare absorbable polymer that can be dissolved in an appropriate lyophilizing solvent.
The final architecture of a polymeric foam made by lyophilization depends on a number of factors, including the polymer concentration in the solvent. Higher mechanical properties often correlate with the bulk density of the foam; high densities then require higher concentrations of the dissolved polymer; for example, 10 weight percent initial solids dissolved in the lyophilizing solvent versus 3 weight percent initial solids. Although a given polymer may be considered soluble in a solvent, it may not be soluble at the high concentrations that may be needed for foam medical devices. Even those absorbable polymers that are soluble in solvents suitable for lyophilization may present another difficulty arising from the phenomena of premature gel formation. Premature gel formation is known to interfere with the making of homogeneous foams, as is required. Premature gelation is particularly challenging in high concentration solutions. It is believed that the gelation phenomena may be due to inter- and intra-chain molecular associations, similar to what might occur during crystallization in solids, although not as strongly. Once gelation takes place in a lyophilizing polymer solution, it is very difficult for polymer chains to possess the mobility they need during the phase separation that must occur as pure solvent (that is solvent without dissolved polymer) crystallizes. Individual chains are “fixed” in place and cannot disentangle to join a solvent/polymer phase of ever increasing polymer concentration.
It has been noted that lyophilizing solutions having higher polymer concentrations may be achieved by lowering the molecular weight of the given polymer, but this has the disadvantage of lowering the mechanical properties of the resultant foam, to unacceptable levels for most surgical applications.
Absorbable polymeric foams to be used in medical applications must typically exhibit dimensional stability, that is, the foams must not deform while undergoing additional, conventional post-processing treatments such as ethylene oxide sterilization, transportation, warehouse storage, and such. This is often a challenge when working with polymers possessing low glass transition temperatures since molecular mobility is enhanced, thereby readily allowing warping, shrinking and other distortions. The crystallization of the polymer constituting the foam is one means of achieving dimensional stability. It should be noted however that a polymer resulting in too high a level of crystallinity in the foam may result in a final article which is too stiff for a given surgical application. For example, the level of “spring back” may be inadequate. Thus, important mechanical properties may be influenced not only by the polymer itself (Tg, etc.) but also by the polymer morphology that develops in the final product, again greatly influenced by the polymer and its thermal history. The level of crystallinity in the resin prior to attempted dissolution is also important in low Tg resins. If the crystallinity is too low the resin pellet (or ground resin) may begin to stick to itself during storage or transportation if exposed to even the slightest elevated temperatures, for example 20° C. The once divided, free-flowing polymer granules gradually aggregate into a large brick-like mass. If the crystallinity of the resin is too high, difficulties may be experienced during attempts to dissolve the resin in the selected solvent; that is, the resin may not properly dissolve.
The lyophilization process is demanding in that it is difficult to produce a suitable product in a robust fashion. If the polymer does not readily dissolve, if it tends to gel too quickly, if it cannot maintain dimensional stability during the process (as well as later during EO sterilization or during transportation), or if the solvent cannot be adequately removed, a suitable foam will not result.
Of course being able to make an absorbable polymeric foam with an appropriate architecture does not complete the challenge; one needs to provide a foam with appropriate ester chemistry to achieve an appropriate hydrolysis profile post-implantation. Retention of mechanical properties for a number of long term surgical applications is critical in slow to heal patients or in slow to heal bodily tissue. Finally, the polymer must still be absorbable; that is, slowly hydrolyze to be removed by the body from the surgical site.
The polymer must then possess certain solubility and crystallization characteristics, as well as certain mechanical and hydrolysis properties, if it is to be suitable for fabricating surgical foam products by the lyophilization method.
The use of some absorbable synthetic polyesters for foam formation via lyophilization processes is known and disclosed in the art. Examples include for example, U.S. Pat. No. 5,468,253, Bezwada, et al., “Elastomeric Medical Device”, filed on Jan. 21, 1993 and issued on Nov. 21, 1995, which discloses medical devices or components for medical devices formed from bioabsorbable elastomers comprising a random copolymer of from about 30 to about 70 weight percent of: a) ε-caprolactone, trimethylene carbonate, and ether lactone, or a mixture of these, and b) the balance being substantially glycolide, para-dioxanone, or a mixture of these. U.S. Pat. No. 5,468,253 further discloses bioabsorbable foams made from the elastomers.
U.S. Pat. No. 6,355,699, Vyakarnam, et al., “Process for Manufacturing Biomedical Foams” filed on Jun. 30, 1999 and issued on Mar. 12, 2002 discloses an improved lyophilization process for forming biocompatible foam structures.
The ε-caprolactone/glycolide copolyesters described by Vyakarnam et al. are directed towards elastomeric materials (see col 5, lines 32 to 36). Their one-step, one-pot polymerization process method tends to produce polymers that exhibit a random distribution of monomer repeat units, while the compositions of the Vyakarnam et al. polyesters made by a sequential addition method, which can be used to produce clearly non-random sequence distributions, are outside the scope of the present invention. In general, the substantially random copolymers of Bezwada, et at and Vyakarnam et al. are quite soluble in at least one lyophilizing solvent, 1,4-dioxane, and only form the undesired gels after an extended period of time. This last characteristic is valuable from a manufacturing standpoint in that it allows significant leeway in processing times. An undesirable characteristic, however, of the random ε-caprolactone/glycolide copolyesters described by Bezwada et al. is that their copolymers are able achieve only low levels of crystallinity. This is a very important characteristic because these copolymers possess relatively low glass transition temperatures and thus do not have the required crystallinity to achieve dimensional stability. During heat treatment (annealing) to purposefully mature the polymer morphology (possibly increase crystallinity levels), it was found that undesirable shrinkage occurred to varying degrees; reliable treatments could not be found to robustly produce acceptable foam product.
Additionally it has been found that lower levels of crystallinity result in a more rapid loss of mechanical properties due to faster hydrolysis of the polymer chains.
Donners et al. in commonly-assigned, co-pending U.S. patent application Ser. No. 14/728226 filed on evendate herewith and incorporated by reference, overcomes these limitations of low crystallinity by preparing Cap/Gly polymers utilizing a staged addition process thus creating glycolide end block capped polymers. This results in retaining a longer functional performance over time and better dimensional stability. However these kind of polymers are only soluble in sufficient concentrations in 1,4-dioxane within a limited range. In addition, the introduction of end blocks, while desirable for performance of the resulting device, leads to more rapid gel formation.
Accordingly, all attempts in the prior art to produce an acceptable medical foam from a gelled polymeric lyophilizing solution [changing freezing rate, drying temperature, etc.] did not result in a foam, let alone a foam useful for medical purposes. The resultant product may appear as a distorted film, not unlike the shape of a potato chip. Thus, specific processing conditions are needed to obtain a thoroughly frozen solution before gel formation occurs in order to achieve a proper foam.
Bioabsorbable films and film formation from bioabsorbable polymeric materials have also been described by various researchers over the years, e.g., U.S. Pat. No. 7,943,683 B2, “Medical Devices Containing Oriented Films of Poly-4-hydroxybutyrate and Copolymers”; U.S. Pat. No. 8,030,434 B2, “Polyester Film, Process for Producing the Same and Use Thereof”; U.S. Pat. No. 4,942,087A, “Films of Wholly Aromatic Polyester and Processes for Preparation Thereof”; U.S. Pat. No. 4,664,859A, “Process for Solvent Casting a Film”; and, U.S. Pat. No. 5,510,176A, “Polytetrafluoroethylene Porous Film”. Various conventional methodologies are known and exist to produce polymeric films. They include melt extrusion, solvent casting, and compression molding. Not all polymers can be easily converted to film products; additionally, different conversion techniques have different challenges. In the case of melt extrusion, the resin must be thermally stable, exhibiting an appropriate melt viscosity, i.e., not too low so as to cause “dripping” and not too high so as to develop excessively high pressures in the extruder, causing instability and non-uniform results. In the case of resins possessing low glass transition temperatures, the dimensional stability of the films made therefrom may be very low if the polymer morphology includes some chain orientation. This is a great driving force for shrinkage and distortion. To circumvent dimensional instability difficulties, the development of a certain amount of crystallinity in the film is advantageous. The rate of crystallization is important in establishing a robust film extrusion process, while the overall level of crystallinity is important in achieving dimensional stability and good mechanical properties. It is known that too low a crystallinity level will result in films which may distort upon ethylene oxide sterilization or upon exposure to even mildly elevated temperatures during processing, transportation, or storage. In a few surgical applications it is desirable for the final films to be strong with appropriate tear resistance, yet pliable enough to possess good handling characteristics.
An absorbable polymer used to manufacture films must possess certain melt and thermal properties, certain crystallization characteristics, as well as certain mechanical and hydrolysis properties, if it is to be suitable for fabricating surgical film products by the melt extrusion process. In the case of films made by solution casting, the polymer resin needs to possess appropriate solubility in a suitable solvent. Suitable solvents advantageously have an appropriate vapor pressure curve leading to suitable evaporation rates, and are generally non-toxic. The polymer must then possess certain solubility and crystallization characteristics, as well as certain mechanical and hydrolysis properties, if it is to be suitable for fabricating surgical film products by a solvent casting process.
Electrostatically spun nonwovens from absorbable polymeric materials are known in the art and have been described by various researchers. See for example U.S. Pat. No. 7,332,050 B2, “Electronic Spinning Apparatus, and a Process of Preparing Nonwoven Fabric Using the Same”; U.S. Pat. No. 7,934,917 B2. “Apparatus for Electro-Blowing or Blowing-Assisted Electro-Spinning technology”; and, U.S. Pat. No. 8,636,942 B2, “Nonwoven Fabric and Process for Producing the Same”. One of the challenges present with electrostatically spun absorbable polymeric nonwovens is that the polymeric material must possess a number of particular characteristics. The polymer must possess adequate solubility in an appropriate solvent to create a suitable spinning dope. The rate of crystallization of the polymer must be appropriate to allow for a robust manufacturing process. The level of crystallinity that can be ultimately developed in the nonwoven fabric made of the polymer must be high enough so as to provide the fabric with appropriate dimensional stability. The level of crystallinity developed also influences the mechanical properties of the fabric. As pointed out earlier, crystallinity levels of the resin can be too high, making solubilization of the resin difficult. Crystallinity levels can also be too high in the fabric, made therefrom, negatively affecting mechanical properties and biological performance. There is a need in this art for novel polymers that provide sufficient mechanical properties long-term, post-implantation; and, novel polymers having glass transition characteristics that provide for softness in finished goods.
Melt-blown nonwoven constructs from absorbable polymeric materials are also known in this art. See for example U.S. Pat. No. 4,769,279A, “Low Viscosity Ethylene Acrylic Copolymers for Nonwovens”; U.S. Pat. No. 8,278,409 B2, “Copolymers of Epsilon-Caprolactone and Glycolide for Melt Blown Nonwoven Applications”; and, U.S. Pat. No. 8,236,904 B2, “Bioabsorbable Polymer Compositions Exhibiting Enhanced Crystallization and Hydrolysis Rates”. One of the challenges with these constructs is that the polymeric material must possess a number of characteristics, including adequate melt viscosity, appropriate rates crystallization, and provide appropriate crystallinity in the finished goods. The polymers need to provide sufficient mechanical properties to the melt-blown constructs long-term, post-implantation, and also provide for softness in finished goods.
Accordingly, there is a need in the art for novel absorbable polymeric foams, films and nonwovens to be used in medical applications.
Specifically in the case of absorbable foams, there is a need to provide retention of mechanical properties post-implantation for extended periods of time, such 64 days or longer. Additionally, there is need to provide foams with improved dimensional stability to avoid warping, shrinking and other distortions during sterilization, storage, transportation, or an exposure to slightly elevated temperatures. Furthermore, there is a need to provide absorbable foams possessing appropriate stiffness, being neither too soft nor too hard, to allow good “spring-back” upon compression; this requires a proper range of crystallinity and Tg.
Further, there is a great need for an absorbable polymer that possesses high solubility characteristics in certain key solvents to avoid gelation during foam formation using the lyophilization method of manufacture.
Finally, there exists a need to provide an absorbable polymer possessing an adequate crystallization rate and the ability to achieve an adequate crystallization level so as to be able to form dimensionally stable foams by the lyophilization process, to form dimensionally stable films by a melt extrusion process, and to form dimensionally stable nonwoven fabrics by either electrostatic spinning or by melt blown processes.